Serum albumin, the protein found in the highest concentration in serum, maintains the osmotic pressure of blood and transports nutritive substances or metabolites bound thereto. A preparation containing the above-mentioned serum albumin is used in the treatment of, for example, hypoalbuminemia caused by the loss of albumin, dysfunction of albumin synthesis and hemorrhagic shock. An albumin preparation in the form of an aqueous solution is heat-treated in order to inactivate viruses which might contaminate the preparation.
The results of gel filtration analysis of a commercially available albumin preparation produced by the above-mentioned method indicate that aggregates were present in said preparation. The aggregates (which are commonly called "polymers" and thus are hereinafter referred to as such) are rarely observed before the above-mentioned heat treatment. Thus, it can be inferred that albumin becomes aggregated upon the heat treatment possibly due to the action of contaminating proteins which are unstable to heat. Since commercially available albumin preparations have been widely and safely used, it is believed that these polymers are harmless to humans. However, it is preferable to minimize the content of polymers in albumin solutions, since the polymers are heat denaturation products.
Further, albumin contains contaminating proteins such as transferrin, the physicochemical properties of which are relatively similar to those of albumin. Since it is difficult to efficiently separate these contaminating proteins from albumin by conventional methods such as fractionation, there is the problem of contamination of an albumin preparation by these proteins.
Various purification methods for preparing serum albumin preparations utilizing ion exchangers are known. That is, a method exists comprising an anion exchanger treatment at a pH in the range of 4.5 to 4.9 followed by a cation exchanger treatment at a pH in the range of 5.2 to 6.5 (U.S. Pat. No. 4,086,222 and FR 2327256), a method exists comprising three steps which comprise a hydrophilic anion exchanger treatment, a hydrophobic anion exchanger treatment and a hydrophilic cation exchanger treatment wherein the hydrophilic cation exchanger is CM-Trisacryl (U.S. Pat. No. 4,675,384 and EP 121468), a method exists which comprises treating an aqueous solution containing serum albumin with an anion exchanger at pH 5.1 to 5.5 for removing a polymer-forming factor present in the solution (U.S. Pat. No. 5,277,818 and EP 367220), and a method exists which comprises treating an aqueous solution containing serum albumin with an anion exchanger and then with a cation exchanger, and subjecting the solution to heat treatment (EP 428758), a method exists which further comprises preserving the aqueous solution containing serum albumin prepared by above-mentioned methods, in a dealkalized soft glass container for keeping the alminium content very low (U.S. Pat. No. 5,372,997 and EP 559895), and a method exists which comprises treating an aqueous solution containing serum albumin with an anion exchanger such as QMA-Sepharosil at pH 4.7 (Bio-Science, Vol. 6, No. 4, p. 103-106 (1987)).
An object of the present invention is to provide a process for producing an albumin preparation which makes it possible to highly purify an albumin, to reduce the content of contaminating proteins, including transferrin, and to lower formation of polymers after heat treatment than the detectable limit as described herein, by improving the purification steps of albumin.